Lung epithelial development is transcriptionally controlled through both positive and negative regulators. Amongst these regulators, the forkhead/winged helix family or Fox family of DMA binding proteins play a central role. Our previous studies have demonstrated that Foxp1/2/4 are potent transcriptional repressors of lung gene transcription and each gene is expressed in overlapping patterns in lung epithelia. We have shown that mouse knock-out models of each of these genes demonstrate unique roles in lung, cardiac, and neural development. In the lung, Foxp2 regulates postnatal alveolarization in part through direct regulation of the alveolar epithelial type 1 cell (AEC-1) gene T1 alpha. In addition to their individual roles in development, recent evidence from our laboratory has demonstrated that Foxp1 and Foxp2 regulate lung airway morphogenesis in a compensatory manner. Foxp1/2/4 are transcriptional repressors and we have demonstrated that these factors link chromatin remodeling to target promoters through interactions with p66, a component of the NuRD (nucleosome remodeling histone deacetylase) complex. Transcriptional repression through complexes such as NuRD and their components including HDAC2 (histone deacetylase 2) are important for surfactant protein gene expression and lung epithelial maturation as our recent data on HDAC2 and the interacting homeodomain only protein (HOP) indicate. These findings demonstrate that Foxp1/2/4 play critical roles in regulation of lung epithelial specific genes, which are required for airway development and postnatal lung homeostasis. However, little is known about whether these factors act redundantly/cooperatively to regulate transcriptional targets in the lung, the mechanism of how Foxp1/2/4 repress lung gene transcription and the effect that loss of these factors has on activation and differentiation of airway progenitor cells including bronchioalveolar stem cells (BASCs) after lung injury. These questions will be addressed in the specific aims of this proposal. [unreadable] [unreadable] [unreadable]